Abstract
Diabetes mellitus (DM) is acknowledged as an independent risk factor for acute kidney injury. Ras guanine nucleotide-releasing protein-4 (RasGRP4) exerts a notable role in modulating immune-inflammatory responses and kidney disease progression in diabetes. Herein, we delved into the specific role and mechanism of RasGRP4 in diabetic renal ischemia-reperfusion injury. Diabetes was induced by a high-fat diet and streptozocin (STZ) injections, followed by creating an ischemia-reperfusion kidney injury via renal pedicle clamping and reperfusion. In vitro, a high glucose and hypoxia-reoxygenation modeled cellular inflammatory injury. We found RasGRP4-KO mice, compared with C57BL/6J (WT) mice, showed markedly less renal dysfunction and fibrosis in diabetic ischemia-reperfusion injury. There was a significant decrease in the renal infiltration of M1 macrophages and Th17 cells, along with downregulated IL-17 pathway proteins and effectors. In vitro, RasGRP4 deletion restrained M1 macrophage polarization and Th17 cell differentiation, inhibiting the IL-17 signaling pathway in HK-2 cells. Hyperglycemia intensified renal inflammation state. Together, RasGRP4, through the regulation of interactions among M1 macrophages, CD4+ T cells, and HK-2 cells, formed a cascade that intensified the inflammatory storm activity, ultimately exacerbating the inflammatory injury of diabetic ischemia-reperfusion kidneys. DM intensified this inflammatory injury mechanism, worsening the injury from renal ischemia-reperfusion.
Authors
Li Zhang, Zhanglong Wang, Yunqi Wu, Binshan Zhang, Zhongli Wang, Sisi Chen, Xuying Meng, Pei Yu, Saijun Zhou
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
Having trouble reading a PDF?
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Having trouble saving a PDF?
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.
Having trouble printing a PDF?
- Try printing one page at a time or to a newer printer.
- Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
- Make sure you are using the latest version of Adobe's Acrobat Reader.
